ES2865058T3 - An improved process for the preparation of (3R, 4R) - (1-benzyl-4-methylpiperidin-3-yl) -methylamine - Google Patents

Abstract

A process for the preparation of 3 - {(3R, 4R) -4-methyl-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] piperidin-1-yl} - 3 -oxo-propanenitrile or a salt thereof comprising: (i) N-acylation of 3-amino-4-methylpyridine with alkyl, aryl or substituted aryl acid chloride or anhydride to prepare a compound of Formula IVa and optionally isolating the compound of Formula IVa; ** (See formula) ** (ii) quaternization of the nitrogen of the pyridine group in the compound of Formula IVa, with benzyl halide or substituted benzyl in a first solvent comprising a first organic solvent to prepare a compound of Formula Va and optionally isolating the compound of Formula Va; ** (See formula) ** (iii) partial reduction of the compound of Formula Va in the presence of a first reducing agent in a second solvent at room temperature to produce a compound of Formula VIa having a system of 1,2, 5,6-tetrahydropyridine; ** (See formula) ** (iv) hydrolysis of the 1,2,5,6-tetrahydropyridine system of the compound of Formula VIa in the presence of an acid or of a mixture of acids to prepare a compound of Formula VIIa; ** (See formula) ** (v) reductive amination of the compound of Formula VIIa with methylamine in the presence of a Lewis acid, in a third solvent comprising a third organic solvent, water, or a mixture thereof; followed by reduction with a second reducing agent at room temperature, to prepare a compound of Formula VIIIa; ** (See formula) ** (vi) resolution of a compound of Formula VIIIa in the presence of a resolution agent, in a fourth solvent comprising a fourth organic solvent, water, or a mixture thereof, to prepare a compound of Formula IIa; and ** (See formula) ** Formula IIa (vii) converting the compound of Formula IIa to 3 - {(3R, 4R) -4-methyl-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin -4-yl) amino] piperidin-1-yl} -3-oxo-propanenitrile; wherein R is selected from hydrogen, alkyl, aryl, or substituted aryl; R 'is selected from aryl or substituted aryl group; and X represents a halide selected from chlorine, bromine and iodine.

Description

DESCRIPTION

An improved process for the preparation of (3R, 4R) - (1-benzyl-4-methylpiperidin-3-yl) -methylamine

Technical field

The present invention provides an efficient and improved process for preparing (3R, 4R) - (1-benzyl-4-methylpiperidin-3-yl) -methylamine; a key starting material for the synthesis of 3 - {(3R, 4R) -4-methyl-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] piperidin-1-yl } -3-oxo-propanenitrile.

Background of the invention

3 - {(3R, 4R) -4-methyl-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] piperidin-1-yl} -3-oxo-propanonitrile, 2 -hydroxypropane-1,2,3-tricarboxylate, described below as FORMULA I and disclosed in WO 02/096909, US7301023. Approved by the US FDA for rheumatoid arthritis.

The key step to prepare 3 - {(3R, 4R) -4-methyl-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] piperidin-1-yl} -3- Oxopropanenitrile as detailed in (Scheme 1) of WO 02/096909 includes:

(i) resolution of racemic (1-benzyl-4-methylpiperidin-3-yl) -methylamine to (3R, 4R) - (1-benzyl-4-methylpiperidin-3-yl) -methylamine using di-p-toluoyl -L-tartarate;

(ii) condensation of 4-chloropyrrolo [2,3-d] pyrimidine with (3R, 4R) - (1 -benzyl-4-methylpiperidin-3-yl) -methylamine to obtain (3R, 4R) - (1 -benzyl -4-methylpiperidin-3-yl) methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine; and

(iii) Debenzylation of (3R, 4R) - (1-benzyl-4-methylpiperidin-3-yl) methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine, followed by condensation with derived from cyanoacetic acid to obtain 3 - {(3R, 4R) -4-methyl-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] piperidin-1-yl} - 3-oxo-propanenitrile (FORMULA I), (Scheme 1).

Scheme 1

The most important part for the preparation of FORMULA I is the synthesis of (3R, 4R) - (1-benzyl-4-methylpiperidin-3-yl) -methylamine, because it is a very tedious synthesis and it also requires a very expensive. Various processes for the synthesis and resolution of racemic (1-benzyl-4-methylpiperidin-3-yl) -methylamine to (3R, 4R) - (1-benzyl-4-methylpiperidin-3-yl) are reported in the literature. ) -methylamine.

Document WO 2007/012953 discloses the preparation of 1-benzyl-3-methoxycarbonyllamine-4-methylpyridine bromide and its asymmetric reduction using mixture of ruthenium-based chiral catalysts under hydrogenation conditions to provide (3R, 4R) - (1-benzyl-4-methylpiperidine- 3-yl) -methylamine with 84% of the isomer c¡s, having 68% ee.

The patent also discloses the preparation of the same intermediate through the application of partial reduction followed by the asymmetric reduction technique. ca, to obtain a very rich derivative of money, as shown in Scheme 2.

Scheme 2

In both techniques, a very high load of chiral catalyst is used, so its commercial use is expensive and difficult. In addition, the process requires a very high pressure, which is dangerous, more expensive and not very suitable for scaling.

WO 2010/123919 provides an additional process for preparing (1-benzyl-4-methylpern-3-¡l) -metalamine, which Includes:

(¡) Protection of the amine group of 3-amino-4-methylpyridine with dimethyl carbonate in the presence of potassium tert-butoxide in tetrahydrofuran;

(¡¡) Quaternization of the nitrogen in the pyridine system by means of benzyl bromide in toluene;

(¡¡¡) Partial reduction of the quaternized pyridine system to produce 1,2,5,6-tetrahydropyridine in the presence of sodium borohydride in methanol;

(V) reduction with plane oxide in methanol provides perjournal derivative. Followed by purification by column chromatography; and

(v) additional reaction with lithium hydride and aluminum and purification by column chromatography to obtain (1-benzyl-4-meth¡lp¡per¡d¡ n-3-¡l) -met¡lam¡na.

The process has several advantages. The overall yield of the process is very low, that is to say, approximately 40%. The process uses two-stage column chromatography. The lithium and aluminum hydride, a known pyrophoric reagent, is responsible for the safety risk during its manufacture. Lastly, plane oxide is highly explosive in the presence of hydrogen. It is a very expensive reagent that does not recommend using it on a plant scale. Overall the process is more expensive, not as safe to operate on a commercial scale, and requires expertise in the most demanding technique.

Furthermore, document WO 2010/123919 shows an additional procedure for preparing (1-benzyl-4-methylpern-3-¡l) -met¡lam The syntactic procedure is summarized in Scheme 3.

Scheme 3

The process involves debenzylation and quaternization of ethyl 1-benzyl-3-oxopiperidin-4-carboxylate, followed by protection of the resulting ethyl 3-oxopiperidine-4-carboxylate derivative, by di-tert-butyl. The protected piperidine derivative was methylated by removing the methylene proton by sodium hydride and further reaction with iodomethane. In the next phase, the deprotection of the W-tert-butoxycarbonyl group was carried out in an acid medium, and the resulting 4-methylpiperidin-3-one was benzylated, followed by reductive amination with methylamine and sodium triacetoxyborohydride to provide the desired product, ( 1-benzyl-4-methylpiperidin-3-yl) -methylamine.

The overall conversion involves five phases from a fairly complex starting product. The process involves protection and unprotection in different phases. The use of expensive and unsafe reagents such as sodium hydride and tear benzyl bromide and sodium triacetoxyborohydride limits their production on a commercial scale. The process has a major drawback with respect to the use of three-stage column chromatography. Furthermore, the disclosure of the process does not say anything about the purity of the intermediates or the target molecule produced. The overall yield mentioned for the process is also very low, ie 13.6 mole percent.

US6627754 provides a reductive amination route similar to that presented in WO 2010/123919 for the synthesis of (1-benzyl-4-methylpiperidin-3-yl) -methylamine from 1-benzyl-4- methylpiperidin-3-one in a tube sealed with sodium triacetoxyborohydride as a reducing agent. Sodium Triacetoxyborohydride is an extremely moisture sensitive pyrophoric reagent. It is difficult to run the sealed tube reaction on a large scale.

The processes learned from the prior art have several drawbacks, namely they are expensive, not suitable for scaling at the plant level, require a lot of energy, difficult, provide lower yields, require the use of corrosive acids, longer duration of corrosive reactions and more difficult to handle. . In view of the drawbacks of the prior art and the very complex methodologies applied, for the preparation of (1-benzyl-4-methylpiperidin-3-yl) -methylamine, there is an urgent and pressing need for a simple process, which save energy, make it cheaper, plant accessible, environmentally friendly process for the preparation of (3R, 4R) - (1-benzyl-4-methylpiperidin-3-yl) -methylamine to synthesize FORMULA I that does not use chemicals that are hygroscopic and pyrophoric and provide even better yields.

Object of the invention

The main object of the present invention is to provide an improved and efficient process for the preparation of (1-benzyl-4-methylpiperidin-3-yl) -methylamine, which has better overall yield.

Another object of the invention is to provide a cost effective, environmentally friendly and energy saving process for preparing (3R, 4R) - (1-benzyl-4-methylpiperidin-3-yl) -methylamine.

Still another object of the invention is to provide a process for the synthesis of (3R, 4R) - (1-benzyl-4-methylpiperidin-3-yl) -methylamine to prepare 3 - {(3R, 4R) -4-methyl- 3-Jmethyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] piperidin-1-yl} -3-oxopropanenitrile, 2-hydroxypropane-1,2,3-tricarboxylate (FORMULA I).

Summary of the invention:

According to the first aspect of the present invention, there is provided an improved and efficient process for the preparation of (3R, 4R) - (1-benzyl-4-methylpiperidin-3-yl) -methylamine, of Formula II.

Another aspect of the present invention is to provide a process for the preparation of a compound of Formula lia, as presented in Scheme 4, comprising:

(i) N-acylation of 3-amino-4-methylpyridine (Formula III) with alkyl, aryl or substituted aryl acid chloride or acid anhydride to obtain Formula IVa;

(ii) quaternization of the nitrogen of the pyridine system having Formula Iva, using benzyl halide or substituted benzyl in an organic solvent or aqueous solvent or mixture (s) thereof to obtain Formula Va;

(iii) Partial reduction of the optionally isolated quartered pyridine system having Formula Va to produce the 1,2,5,6-tetrahydropyridine system of Formula VIa in the presence of a reducing agent or any borohydride agent in an organic solvent or aqueous solvent or mixture (s) thereof, at room temperature;

(iv) hydrolysis of the 1,2,5,6-tetrahydropyridine system of Formula VIa in the presence of an acid or a mixture of acids to obtain Formula VIIa, at room temperature;

(v) reductive amination of Formula VIIa by methylamine in the presence of any Lewis acid in an organic solvent or aqueous solvent or mixture (s) thereof, followed by reduction using any reducing agent or any alkali metal borohydride derivative produces the compound of Formula VIIIa, at room temperature; and

(vi) further resolution of compound VIIIa in the presence of any resolution agent in an organic solvent or aqueous solvent or mixture (s) thereof produces the compound of Formula IIa.

Scheme 4

Formu a Formu a Va Formu a Va Formu a V a

Formu a V a Formu a V a Formu a a

wherein R represents hydrogen, alkyl, aryl, substituted aryl, and R 'represents aryl or substituted aryl group.

Prior art document WO 2010/123919 uses reagents from different classes of compounds. The two routes of synthesis (ROS) are different. WO 2010/123919 does not contemplate the use of anhydride in the first step. The intermediate that is formed in the reaction of the present invention has a methyl in the side chain, which was not the case in the prior art. The initial use of different classes of reagents in the present invention produces different classes of intermediates. The hydrolysis and reductive amination steps and intermediates formed are unique to the ROS of the present invention. They are not found in the prior art. Lithium aluminum hydride is essential in WO 2010/123919, but is not used in the present invention. Furthermore, the inventive step of the present invention also resides in a surprising reduction in the duration of various steps of the reaction, compared to those of WO 2010/123919. The preparation of the 1,2,5,6-tetrahydropyridine system of Formula VIa can be completed in 30% of the time required for WO 2010/123919.

Still another aspect of the present invention is to provide a process for the preparation of (3R, 4R) - (1-benzyl-4-methylpiperidin-3-yl) -methylamine of Formula (II), as presented in Scheme 5 , comprising:

(i) N-acylation of 3-amino-4-methylpyridine with acetyl chloride or with acetic anhydride to obtain Formula IV;

(ii) quaternization of the nitrogen of the pyridine system having Formula IV, using benzyl chloride in the presence of toluene to obtain Formula V;

(iii) partial reduction of the optionally isolated quaternized pyridine system of Formula V to produce the 1,2,5,6-tetrahydropyridine system of Formula VI in the presence of sodium borohydride in methanol or in water, to obtain Formula VI, to environmental temperature;

(iv) hydrolysis of the 1,2,5,6-tetrahydropyridine system of Formula V in the presence of a mixture of hydrochloric acid and acetic acid to obtain Formula VII, at room temperature;

(v) reductive amination of Formula VII in the presence of titanium (IV) tetraisopropoxide in methylamine, followed by reduction with sodium borohydride to obtain 1- (benzyl-4-methylpiperidin-3-yl) -methylamine of Formula VIII, at temperature environmental; and

(vi) further resolution of the compound of Formula VIII in the presence of a resolving agent such as dibenzoyl-L-tartaric acid or ditoluoyl-L-tartaric acid in the mixture of methanol and / or water to produce (3R, 4R) - (1-Benzyl-4-methylpiperidin-3-yl) -methylamine of Formula II.

Scheme 5

Formula Formula IV Formula V Formula VI

Formula VII Formula VIII Formula

Reagent: (i) acetyl chloride, acetic acid, room temperature; (ii) benzyl chloride, toluene, 110 ° C; (iii) sodium borohydride, methanol, 0 ° C to 5 ° C or sodium borohydride, water, 0 ° C to 5 ° C; (iv) HCl, AcOH, from 80 ° C to 85 ° C; (v) titanium (IV) tetraisopropoxide, methanolic methylamine, NaBH4, MeOH, 0 ° C to 5 ° C; (vi) ditoluoyl-L-tartaric acid, MeOH-water (1: 1)

Detailed description of the invention

The present invention relates to an improved and efficient process for the preparation of the compound of formula (Ila), comprising:

(i) N-acylation of 3-amino-4-methylpyridine (Formula III) with alkyl, aryl or substituted aryl acid chloride or acid anhydride to obtain Formula IVa;

(ii) quaternization of the nitrogen of the pyridine system having Formula IVa, using benzyl or substituted benzyl halide in an organic solvent to obtain Formula Va;

(iii) partial reduction of the quaternized pyridine system having Formula Va to produce the 1,2,5,6-tetrahydropyridine system of Formula VIa in the presence of a reducing agent or any borohydride agent in an organic solvent, to environmental temperature;

(iv) hydrolysis of the 1,2,5,6-tetrahydropyridine system of Formula VIa in the presence of an acid or of a mixture of acids to obtain Formula VIIa, at room temperature;

(v) reductive amination of Formula VIIa by methylamine in the presence of any Lewis acid in an organic solvent or aqueous solvent or mixture (s) thereof, followed by reduction with any reducing agent or with any derivatives of metal borohydrides alkaline produces the compound of Formula VIIIa, at room temperature; and

(vi) further resolution of compound VII Ia in the presence of any resolution agent in an organic solvent or aqueous solvent or mixture (s) thereof produces the compound of Formula I Ia.

C1 acid anhydride is acetic acid anhydride, ie acetic anhydride. C2 acid anhydride is an anhydride of propanoic acid. C1-10 acid anhydrides can be used in the present invention. C1-10 acid chloride is to be understood as acid chloride of formic acid to decanoic acid, aryl acid chlorides or substituted acid chlorides having up to 10 carbon atoms. C1-C5 alcohols are to be understood as methanol, ethanol, propanol, butanol, and pentanol. A better overall yield should be interpreted as an overall yield of more than 50% for the synthesis of 1-benzyl-4-methylpiperidin-3-yl) -methylamine, a pre-resolution intermediate.

The terms quaternization and quaternization are used interchangeably and have the same meaning with respect to tertiary nitrogen bonding. The terms improved and effective should be understood in the sense of better yields, lower energy expenditure, reactions of shorter duration, in addition to reduced costs of the inputs and simplicity of the procedures involved, better scalability at the plant level. The pyridine system refers to the part of the pyridine ring in the molecular structure, with or without substituents. Ambient temperature should be understood as the temperature between 0 ° C and 30 ° C. RT is room temperature. The terms chloride Methylene and methylene dichloride, ie, MDC, are used interchangeably. The inventive step of the present invention resides in (Scheme 6):

(i) N-acylation of 3-amino-4-methylpyridine (Formula III) with alkyl, with alkyl, aryl or substituted aryl acid chloride or acid anhydride to obtain Formula IVa. In the prior art there was no acetylation reaction at this stage. The prior art shows the use of dimethyl carbonate and, due to the difference in the reagents of this initial phase, structurally different intermediates are formed, which belong to different classes of chemical compounds that show different properties;

(ii) quaternization of the nitrogen of the pyridine system having Formula IVa, using benzyl halide or substituted benzyl in an organic solvent to obtain Formula Va;

(iii) Partial reduction of the optionally isolated quartered pyridine system having Formula Va to produce the 1,2,5,6-tetrahydropyridine system of Formula VIa in the presence of a reducing agent or any borohydride agent in an organic solvent at room temperature;

(iv) hydrolysis of the 1,2,5,6-tetrahydropyridine system of Formula VIa in the presence of an acid or a mixture of acids to achieve Formula VIIa at room temperature; and

(v) reductive amination of Formula VIIa using methylamine in the presence of any Lewis acid in an organic solvent or aqueous solvent or mixture (s) thereof, followed by reduction using any reducing agent or any derivatives of alkali metal borohydrides produces the compound of Formula VIIIa at room temperature.

Scheme 6

wherein R represents hydrogen, alkyl, aryl, substituted aryl and R 'represents benzyl or substituted arylbenzyl group. N-acylation of 3-amino-4-methylpyridine (Formula III) with alkyl, aryl, or substituted aryl acid anhydride includes C1-10 anhydride, acetic anhydride, and more preferably acetic anhydride.

N-acylation of 3-amino-4-methylpyridine (Formula III) with alkyl, aryl or substituted aryl acid chloride includes C1-10 acid chloride, acetyl chlorides, benzoyl chloride, etc. more preferably acetyl chloride. N acylation leads to the formation of the compound of formula (IVa) and salts thereof,

wherein R represents C1-C10 alkyl, aryl, or substituted aryl, but does not include isopropyl or phenyl. When R represents C3-C10 alkyl, aryl or substituted aryl, but does not include isopropyl or phenyl; novel compounds are formed.

The quaternization of the nitrogen of the pyridine system having the Formula IVa, using benzyl halide or substituted benzyl includes benzyl chloride, benzyl bromides, etc. more preferably benzyl chloride.

The quaternization of the nitrogen of the pyridine system having Formula IVa, to obtain Formula Va, is carried out using benzyl halide or substituted benzyl halide in the presence of an organic or aqueous-organic solvent including toluene, xylenes, alcoholic solvents or solvents. of ether, more preferably toluene and xylenes, most preferably toluene. Polar, protic, aprotic solvents should be interpreted according to prevailing definitions.

The quaternization of the nitrogen of the pyridine system having the Formula IVa, using benzyl halide or substituted benzyl in the presence of an organic solvent to obtain the Formula Va was carried out at a temperature between 40 ° C and 110 ° C, more preferably between 75 ° C. and 852C. A compound of the formula (Va)

wherein R represents alkyl, aryl or substituted aryl, more preferably methyl; R 'represents aryl or substituted aryl group, more preferably phenyl; and X represents the group of the halides such as chlorine, bromine, iodine, or any leaving group such as tosyloxy or mesyloxy.

Partial reduction of the quartered pyridine system of Formula Va produces the 1,2,5,6-tetrahydropyridine system of Formula Via, in the presence of a reducing agent such as a borohydride agent including sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride , more preferably sodium borohydride and the organic solvent selected from the group consisting of alcoholic solvents such as methanol, ethanol, ether solvents such as diisopropyl ether (DIPE), methyl tert-butyl ether (MTB) or toluene, xylenes or aqueous mixture of same, more preferably methanol, water, most preferably water. The reduction using the borohydride reagent was carried out between 0 ° C and 10 ° C, more preferably between 0 ° C and 5 ° C.

The 1,2,5,6-tetrahydropyridine system of Formula Via can be obtained from the pyridine system having Formula IVa by optionally isolating the quartered pyridine system having Formula Va. A compound of formula (VIa) and salts thereof

wherein R represents alkyl, aryl or substituted aryl, more preferably methyl;

R 'represents aryl or substituted aryl group, more preferably phenyl.

Hydrolysis of the 1,2,5,6-tetrahydropyridine system of Formula VIa in the presence of an acid or a mixture of acids including hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, trichloroacetic acid, acetic acid, or aqueous solutions thereof or mixture (s) thereof, more preferably hydrochloric acid and acetic acid, most preferably mixture of hydrochloric acid and acetic acid.

The hydrolysis of the 1,2,5,6-tetrahydropyridine system of Formula Via was carried out in the presence of an acid or a mixture of acids at a temperature between 40 ° C and 110 ° C, more preferably between 75 ° C. C and 90 ° C, most preferably between 85 ° C and 90 ° C.

The reductive amination of Formula Viia can be carried out using methylamine in the presence of any Lewis acid such as AlCl ³ , InCl ³ , titanium (IV) tetraisopropoxide, FeCl ³ , etc., more preferably titanium (IV) tetraisopropoxide.

The reductive amination of Formula Viia can be carried out using methylamine in the presence of any Lewis acid in an organic solvent such as alcoholic solvent such as methanol, ethanol or ether solvents such as diisopropyl ether (DiPE), methyl tert-butyl ether (MTB ) or toluene, xylenes or aqueous mixture (s) thereof, more preferably methanol or water, most preferably water.

Reductive amination of Formula Viia using methylamine in the presence of any Lewis acid in an organic solvent followed by reduction using any reducing agent such as alkali metal borohydride derivatives, including sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, more preferably sodium borohydride to produce Formula Viiia.

The reductive amination of the Formula Viia using methylamine in the presence of any Lewis acid in an organic solvent followed by reduction using any reducing agent or any derivative of alkali metal borohydrides to obtain the compound of Formula Viiia was carried out at a temperature of between 0 ° C and 10 ° C, more preferably between 0 ° C and 5 ° C.

Resolution of Formula Viiia in the presence of a resolving agent including tartaric acid, dibenzoyl tartaric acid (DBTA), ditoluoyl tartaric acid (DTTA), mandalic acid, camphorsulfonic acid, etc., more preferably dibenzoyl tartaric acid (DBTA), acid ditoluoyl tartaric acid (DTTA), most preferably ditoluoyl tartaric acid (DTTA) to obtain the compound of Formula iia.

Resolution of Compound Viiia in the presence of any resolving agent in an organic solvent includes an alcoholic solvent such as methanol, ethanol, ether solvents, toluene, xylenes, or aqueous mixture (s) thereof, more preferably methanol for obtain the compound of Formula iia. Ether solvents include diisopropyl ether (DiPE), methyl tert-butyl ether (MTB), but are not limited to just these two solvents. The invention is further illustrated in connection with the following examples.

Examples

EXAMPLE 1: Preparation of N- (4-methylpyridin-3-yl) -acetamide from 3-amino-4-methylpyridine

3-Amino-4-methylpyridine (200 g) and acetic acid (600 ml) were charged into a 2 L, 4-necked round bottom flask with a stirrer on top, and stirred for 15 min at RT . Acetic anhydride (284 g / 263 ml) or acetyl chloride (174 g) were added dropwise over 1-2 h at that temperature. The reaction mass was then stirred at RT for 8-10 hours. After completion of the reaction monitored by TLC, HPLC; acetic acid was distilled off in vacuo. Methanol (1 L) was then added to the reaction mixture and the pH of the reaction mixture was kept around 10-12 with liquid ammonia. Methanol was completely vacuum distilled at 50 ° C to 55 ° C. The product was then extracted with MDC (1 L) to obtain the pure product. Yield: 98% w / w; Purity by HPLC: 98%.

EXAMPLE 2: Preparation of N- (4-methylpyridin-3-yl) -acetamide from 3-amino-4-methylpyridine

3-Amino-4-methylpyridine (200 g) and acetic anhydride (284 g / 263 ml) were stirred in a 2 L, 4-necked round bottom flask with an overhead stirrer for 15 minutes at RT. . Stirring was continued at RT for 1-3 h. After completion of the reaction monitored by TLC, methanol (1 L) was added to the reaction mixture and the pH of the reaction mixture was kept around 10-12 with liquid ammonia. Methanol was completely vacuum distilled at 50 ° C to 55 ° C. Extraction with MDC (1 L) provided the pure product. Yield: 98% w / w; Purity by HPLC: 98%.

EXAMPLE 3: Preparation of N- (4-methylpyridinium-3-yl) -acetamide acetate from 3-amino-4-methylpyridine

3-Amino-4-methylpyridine (200 g), acetic anhydride (284 g / 263 ml) or acetyl chloride (174 g) and MDC (1 L) were stirred in a 2 L, 4 neck round bottom flask. , with an overhead shaker, for 15 minutes at RT. The reaction mass was stirred at RT for 8-10 h. Completion of the reaction was monitored by TLC, HPLC. Extraction with MDC (1 L) provided the pure product. Yield: 98% w / w; Purity by HPLC: 98%.

EXAMPLE 4: Preparation of N- (4-methylpyridin-3-yl) -acetamide from 3-amino-4-methylpyridine

3-Amino-4-methylpyridine (200 g) and acetic anhydride (284 g / 263 ml) or acetyl chloride (174 g) and MDC (1 L) were stirred in a 2 L, 4 neck round bottom flask. , with an overhead shaker, for 15 minutes at RT. Then the reaction mass was stirred at RT for 8-10 hours. Completion of the reaction was monitored by TLC. The pH of the mixture was kept around 10-12 with liquid ammonia. Extraction with MDC (1 L) provided the pure product. Yield: 98% w / w; Purity by HPLC: 98%.

EXAMPLE 5: Preparation of 1-benzyl-4-methyl-1,2,5,6-tetrahydropyridin-3-yl-acetyl amine from N- (4-methylpyridin-3-yl) -acetamide

Toluene (1 L) and N- (4-methylpyridin-3-yl) -acetamide (200 g) were charged into a 2 L, 4-necked round bottom flask with a stirrer on top, and stirred for 15 minutes at RT. Benzyl chloride (202 g) or benzyl bromide (273 g) were added to the insoluble reaction mass and stirred for 15 minutes at RT. The temperature of the reaction mass was raised to 80 ° C to 85 ° C and stirred until the reaction was complete (monitored by TLC, HPLC). The reaction mass was then cooled to 25 ° C to 30 ° C and the toluene phase was decanted. Methanol (1 L) was charged to the reaction mixture, stirred to a clear solution, and cooled to 0 ° C to 5 ° C. Sodium borohydride solution (60 g in 0.1 N sodium hydroxide) was added dropwise at 0 ° C to 5 ° C. The reaction mixture was then stirred for 10-12 hrs, as required to complete the reaction (monitored by TLC, HPLC). Water (600 ml) was added to the reaction mass and stirred until a clear solution was obtained. Methanol was distilled off in vacuo. The solid precipitate that was observed was filtered with a Buckner funnel to obtain the pure product. (Yield = 84-87%; HPLC: 90%).

EXAMPLE 6: Preparation of 1-benzyl-4-methyl-1,2,5,6-tetrahydropyridin-3-yl-acetyl amine from N- (4-methylpyridin-3-yl) -acetamide

Toluene (1 L) and N-acetyl-3-amino-4-methylpyridine (200 g) were charged to a 2 L, 4-necked round bottom flask with a stirrer on top, and stirred for 15 minutes at RT. Benzyl chloride (202 g) or benzyl bromide (273 g) were added to the insoluble reaction mass and stirred for 15 minutes at that temperature. Then, the temperature of the reaction mass was raised to 80 ° C to 85 ° C and the reaction mixture was stirred at that temperature for 8-10 h, as required for the reaction to complete (monitored by TLC, HPLC). The reaction mass was cooled to 25 ° C to 30 ° C. Water (1 L) was charged to the reaction mixture and stirred for 15 minutes. The aqueous phase was separated and cooled to 0 ° C to 5 ° C. Then, sodium borohydride solution (60 g in 0.1 N sodium hydroxide) was added to the aqueous phase dropwise at 0 ° C to 5 ° C. The reaction mixture was then stirred for 10-12 h to complete the reaction (monitored by TLC, HPLC). After the completion of the reaction, the solid precipitate that was observed was filtered with a Buckner funnel to obtain the pure product. (Yield = 84-87%; HPLC: 90%)

EXAMPLE 7: Preparation of Quarternized Benzyl Salt of N- (4-methylpyridIn-3-yl) -acetamide

Toluene (1 L), N- (4-methylpyridin-3-yl) -acetamide (200 g) were charged into a 2 L, 4-necked round bottom flask with a stirrer on top, and stirred for 15 minutes at RT. Benzyl chloride (202 g) or benzyl bromide (273 g) were added to the insoluble reaction mass and stirred for 15 minutes at that temperature. The temperature of the reaction mass was then raised to 80 ° C to 85 ° C and stirred for 8-10 h for completion of the reaction (monitored by TLC, HPLC). Then, the reaction mass was cooled to 25 ° C to 30 ° C and the toluene phase was filtered to obtain N- (4-methylpyridin-3-yl) -acetamide quartered benzyl salt (Yield = 98%; HPLC : 95%)

EXAMPLE 8: Preparation of 1-benzyl-4-methyl-1,2,5,6-tetrahydropyridine-3-yl-acetylamine from quartz benzyl salt of N- (4-methylpyridin-3-yl) -acetamide

Methanol (1 L), N- (4-methylpyridin-3-yl) -acetamide (200 g), quartnerized benzyl salt was charged into a 2 L, 4-necked round bottom flask with a stirrer at the bottom. up, and stirred for 15 min at RT. The reaction mixture was cooled to 0 ° C to 5 ° C and sodium borohydride solution (60 g in 0.1 N sodium hydroxide) was added dropwise at that temperature. It was stirred for 10-12 h to complete the reaction (monitored by TLC, HPLC). After the reaction was complete, water (600 ml) was added and stirred until a clear solution was obtained. Methanol was distilled off in vacuo. The solid precipitate that was observed was filtered to obtain the pure product. (Yield = 75%; HPLC: 98%).

EXAMPLE 9: Preparation of 1-benzyl-4-methyl-1,2,5,6-tetrahydropyridine-3-yl-acetylamine from 3-amino-4-methylpyridine

3-Amino-4-methylpyridine (200 g) and acetic anhydride (284 g / 263 ml) were charged into a 2 L, 4-necked round bottom flask with a stirrer on top, and stirred at 25 ° C to 30 ° C for 1-3 h. After the completion of the reaction monitored by TLC, methanol (1 L) was added to the reaction mixture and the pH was maintained around 10-12 with liquid ammonia. Methanol was completely distilled in vacuo at 50 ° C to 55 ° C. The product was then extracted with MDC (1 L) and the organic phase was distilled to obtain crude N- (4-methylpyridin-3-yl) -acetamide.

Toluene (1 L) was charged to the reaction mixture and stirred for 15 minutes at RT. Benzyl chloride (202 g) or benzyl bromide (273 g) were added to the insoluble reaction mass and stirred for 15 minutes at that temperature. The temperature was then raised to 80 ° C to 85 ° C and the reaction mixture was stirred at that temperature for 8-10 hrs as required to complete the reaction (monitored by TLC, HPLC). Dough cooled of the reaction up to 25 ° C to 302C. Next, water (1 L) was charged to the reaction mixture and stirred for 15 minutes. The aqueous phase was separated and cooled to 0 ° C to 5 ° C. Sodium borohydride solution (60 g in 0.1 N sodium hydroxide) was added dropwise to the aqueous phase at 0 ° C to 5 ° C. The reaction mixture was then stirred for 10-12 hrs, as required to complete the reaction (monitored by TLC, HPLC). After completion of the reaction, the solid precipitate that was observed was filtered with a Buckner funnel to obtain the pure product. (Yield = 84-87%; HpLC: 90%).

EXAMPLE 10: Preparation of N-benzyl-4-methylpiperidin-3-one from 1-benzyl-4-methyl-1,2,5,6-tetrahydropyridin-3-ylacetylamine

Acetic acid (50 ml), and conc. HCl were charged. 35% (100 ml) into a 2 L, 4 necked round bottom flask with a stirrer on top, and stirred for 10 min at RT. Next, 1 -benzyl-4-methyl-1,2,5,6-tetrahydropyridin-3-yl-acetylamine (100 g) was added to the reaction mass at that temperature. The temperature of the reaction mass was slowly raised to 85 ° C to 90 ° C and stirred for 3-4 h at that temperature, as required to complete the reaction (monitored by TLC, HPLC). The reaction mixture was cooled to 25 ° C to 30 ° C and extracted with toluene (500 ml) to obtain the pure product. Yield: 95%; HPLC: 95%

EXAMPLE 11: Preparation of N-benzyl-4-methylpiperidin-3-one from 1-benzyl-4-methyl-1,2,5,6-tetrahydropyridin-3-ylacetylamine

Conc. HCl were loaded. 35% (150 ml) and 1 -benzyl-4-methyl-1,2,5,6-tetrahydropyridin-3-yl-acetylamine (100 g) in a 2 L, 4-neck round bottom flask with a shaker on top, and stirred for 10 min at RT. The temperature of the reaction mixture was slowly raised to 85 ° C to 90 ° C and stirred for 3-4 h to complete the reaction (monitored by TLC, HPLC). Then, the reaction mixture was cooled to 25 ° C to 30 ° C and extracted with toluene (500 ml) to obtain the pure product. Yield: 95%; HPLC: 90%.

EXAMPLE 12: Preparation of N-benzyl-4-methylpiperidin-3-one from 1-benzyl-4-methyl-1,2,5,6-tetrahydropyridin-3-ylacetylamine

Acetic acid (100 ml) and 1-benzyl-4-methyl-1,2,5,6-tetrahydropyridin-3-yl-acetylamine (100 g) were charged into a 2 L, 4 necked round bottom flask, with an overhead stirrer, and stirred for 15 minutes at RT. The temperature of the reaction mixture was slowly raised to 85 ° C to 90 ° C and stirred for 3-4 h to complete the reaction (monitored by TLC, HPLC). Then, the reaction mixture was cooled to 25 ° C to 30 ° C and extracted with toluene (500 ml) to obtain the pure product. Yield: 95%; HPLC: 90%.

EXAMPLE 13: Preparation of (1-benzyl-4-methylpiperidin-3-yl) -methylamine from N-benzyl-4-methylpiperidin-3-one

Methanol (500 ml) and N-benzyl-4-methylpiperidin-3-one (100 g) were charged to a 2 L, 4 necked round bottom flask with a stirrer on top, and stirred for 15 minutes at RT. The reaction mass was cooled to 0 ° C to 5 ° C and titanium (IV) tetraisopropoxide solution (175 ml) was added dropwise over 30-45 minutes. The reaction mass was stirred at 0 ° C to 5 ° C for 30 minutes and methanolic methylamine solution (30%) (100 ml) was added dropwise at 0 ° C to 5 ° C over the course of 30-45 minutes. The reaction mass was stirred for 2-3 h at 0 ° C to 5 ° C. Sodium borohydride (22 g) was then added to the reaction mass over 30-45 minutes at 0 ° C to 5 ° C and stirred for 2-3 h. After the reaction was complete, monitored by TLC, HPLC; Water (500 ml) was added to the reaction mixture and it was stirred for 30-45 minutes at RT. The product was extracted using MDC (500 ml) to obtain the pure product. Yield: 90%; HPLC: 90%.

EXAMPLE 14: Preparation of (1-benzyl-4-methylpiperidin-3-yl) -methylamine from N-benzyl-4-methyl-3-piperidone

Methanol (500 ml) and N-benzyl-4-methylpiperidin-3-one (100 g) were charged into a 2 L, 4 necked round bottom flask with a stirrer on top. It was stirred for 15 minutes at RT. The reaction mass was cooled to 0 ° C to 5 ° C and titanium (IV) tetraisopropoxide solution (175 ml) was added dropwise over 30-45 minutes. The reaction mass was stirred at 0 ° C to 5 ° C for 30 minutes and methylamine hydrochloride was added at 0 ° C to 5 ° C over 30-45 minutes. The reaction mass was stirred for 2-3 h at 0 ° C to 5 ° C. Sodium borohydride (22 g) was added to the reaction mass over 30-45 minutes at 0 ° C to 5 ° C and stirred for 2-3 h. After the reaction was complete, monitored by TLC, HPLC; Water (500 ml) was added to the reaction mass and stirred for 30-45 minutes at RT. The product was extracted with MDC (500 ml) to obtain the pure product. Yield: 95%; HPLC: 90%.

EXAMPLE 15: Resolution of (1-benzyl-4-methylpiperidin-3-yl) -methylamine to obtain (3R, 4R) - (1-benzyl-4-methylpiperidin-3-yl) -methylamine

Methanol (500 ml) and (1-benzyl-4-methylpiperidin-3-yl) -methylamine (100 g) were charged into a 2 L, 4-necked round bottom flask with a stirrer on top, and stirred for 15 minutes at RT. Ditoluoyl-L-tartaric acid (DTTA) (106 g) or dibenzoyl-L-tartaric acid (DBTA) (98 g) was added to the reaction mixture and stirred for 15 minutes until a clear solution was obtained. Water (500 ml) was added to the reaction mass and the temperature was raised to 65 ° C to 70 ° C and stirred for 1 hr. The reaction mass was cooled to 10 ° C to 15 ° C and held for 3 h. The precipitated solid was filtered to obtain ditoluoyl-L-tartaric acid (DTTA) or acid (3R, 4R) - (1-Benzyl-4-methylpiperidin-3-yl) -methylamine pure dibenzoyl-L-tartaric (DBTA). Yield = 80-82%; HPLC: 98%.

Although the invention has been described with reference to specific embodiments, it is not intended to be construed in a limiting sense. Various modifications of the disclosed embodiments and alternative embodiments of said invention will be apparent to those skilled in the art upon reference to the description of the invention.

Claims (17)

1. A process for the preparation of 3 - {(3R, 4R) -4-methyl-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] piperidin-1-yl} -3-oxo-propanenitrile or a salt thereof comprising: (i) N-acylation of 3-amino-4-methylpyridine with alkyl, aryl or substituted aryl acid chloride or acid anhydride to prepare a compound of Formula IVa and optionally isolate the compound of Formula IVa;

(ii) quaternization of the nitrogen of the pyridine group in the compound of Formula IVa, with benzyl halide or substituted benzyl in a first solvent comprising a first organic solvent to prepare a compound of Formula Va and optionally isolate the compound of Formula Va;

(iii) partial reduction of the compound of Formula Va in the presence of a first reducing agent in a second solvent at room temperature to produce a compound of Formula VIa having a 1,2,5,6-tetrahydropyridine system;

(iv) hydrolysis of the 1,2,5,6-tetrahydropyridine system of the compound of Formula VIa in the presence of an acid or a mixture of acids to prepare a compound of Formula VI Ia;

(v) reductive amination of the compound of Formula VI Ia with methylamine in the presence of a Lewis acid, in a third solvent comprising a third organic solvent, water, or a mixture thereof; followed by reduction with a second reducing agent at room temperature, to prepare a compound of Formula VIIIa;

(vi) resolving a compound of Formula Villa in the presence of a resolving agent, in a fourth solvent comprising a fourth organic solvent, water, or a mixture thereof, to prepare a compound of Formula 1a; and

Formula lia (vii) converting the compound of Formula lia to 3 - {(3R, 4R) -4-methyl-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] piperidin-1 - yl} -3-oxo-propanenitrile; wherein R is selected from hydrogen, alkyl, aryl, or substituted aryl; R 'is selected from the group aryl or substituted aryl; and X represents a halide selected from chlorine, bromine and iodine. 2. The process of claim 1 wherein the N-acylation of part (i) is an acid anhydride C ^{1 to 10.} 3. The process of claim 1 wherein the N-acylation of part (i) is an acid chloride C ^1-10. 4. The process of claim 1, wherein the quaternization of part (ii) is with benzyl chloride, benzyl bromide, substituted benzyl chloride or substituted benzyl bromide. The process of claim 1, wherein the first organic solvent comprises one or more of an aromatic solvent, a polar aprotic solvent, a non-polar solvent solvent, an ether solvent, an ester solvent, or a solvent of ketone, and the first solvent optionally comprises water. 6. The process of claim 5, wherein the first organic solvent is selected from the group consisting of toluene, xylene, cyclohexane, and a mixture thereof. 7. The process of claim 6, wherein the first organic solvent is selected from toluene, xylene, and a mixture thereof. 8. The process of claim 1, wherein the first and second reducing agents are independently selected from the group consisting of sodium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride. The process of claim 1, wherein the second solvent is selected from the group consisting of water, C ¹ -C ⁵ alcohol, diisopropyl ether, methyl tert-butyl ether, toluene, xylene, and a mixture thereof. 10. The process of claim 1, wherein the acid or acid mixture of part (iv) is selected from hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, trichloroacetic acid, halo substituted acetic acid, acetic acid, Hl , HBr, mineral acids, organic acids, aqueous solutions or a mixture thereof. The process of claim 1, wherein the Lewis acid of part (v) is selected from the group consisting of aluminum trichloride, ferric chloride, zinc chloride, indium chloride, and titanium tetraisopropoxide (IV). The process of claim 1, wherein the resolving agent of part (vi) is selected from the group consisting of dibenzoyl tartaric acid, ditoluoyl tartaric acid, tartaric acid, mandelic acid, and camphor camphor sulfonic acid. The process of claim 1, wherein the hydrolysis in part (iv) is carried out at a temperature in the range of from 40 ° C to 110 ° C. The process of claim 1, wherein the third organic solvent comprises methanol, ethanol, diisopropyl ether, methyl tert-butyl ether, toluene, xylene, or a mixture thereof, and the third solvent optionally comprises water. The process of claim 1, further comprising converting 3 - {(3R, 4R) -4-methyl-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] piperidin-1-yl} -3-oxo-propanonitrile to 3 - {(3R, 4R) -4-methyl-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] piperidin -1 -yl} -3-oxo-propanenitrile, 2-hydroxypropane-1,2,3-tricarboxylate. 16. The process of claim 1, further comprising isolating the compound of Formula IVa. 17. The process of claim 1, further comprising isolating the compound of Formula Va.